Urinary Elimination of Coproporphyrins Is Dependent on ABCC2 Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans

MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient

: Gender differences in STEMI

International audienceBACKGROUND: Gender differences in presentation, management and outcome in patients with ST-segment elevation myocardial infarction (STEMI) have been reported. AIM: To determine whether female gender is associated with higher inhospital mortality. METHODS: Data from ORBI, a regional STEMI registry of 5 years' standing, were analysed. The main data on presentation, management, inhospital outcome and prescription at discharge were compared between genders. Various adjusted hazard ratios were then calculated for inhospital mortality (women versus men). RESULTS: The analysis included 5000 patients (mean age 62.6±13 years), with 1174 women (23.5%). Women were on average 8 years older than men, with more frequent co-morbidities. Median ischaemia time was 215 minutes (26 minutes longer in women; P<0.05). Reperfusion strategies in women less frequently involved fibrinolysis, coronary angiography, radial access and thrombo-aspiration. Female gender, especially in patients aged<60 years, was associated with poorer inhospital prognosis (including higher inhospital mortality: 9% vs. 4% in men; P<0.0001), and underutilization of recommended treatments at discharge. Moreover, excess female inhospital mortality was independent of presentation, revascularization time and reperfusion strategy (hazard ratio for women 1.33, 95% confidence interval 1.01-1.76; P=0.04). CONCLUSIONS: One in four patients admitted for STEMI was female, with significant differences in presentation. Female gender was associated with less-optimal treatment, both in the acute-phase and at discharge. Efforts should be made to reduce these differences, especially as female gender was independently associated with an elevated risk of inhospital mortality

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Growth in preterm and neurologic outcome : association between growth before and after birth and neurologic outcome in extreme preterm newborn from epipage cohort study

Les objectifs de cette thèse étaient de définir le retard de croissance intra-utérin chez le nouveau-né prématuré, d’étudier ses conséquences en terme de morbidité néonatale et de pronostic à long terme et d’évaluer les liens existant entre retard de croissance intra-utérin, croissance extra-utérine et pronostic des prématurés. Nous avons mis en évidence dans un premier temps que le seuil strict de définition d’un « nouveau-né petit pour l’âge gestationnel» ne pouvait se limiter dans le cadre de la prématurité au 10ème percentile mais s’étendre au-delà, au moins jusqu’au 20ème percentile. Par ailleurs, se limiter au poids n’était pas suffisant et qu’une définition par l’association entre poids et périmètre crânien était pertinente en terme de pronostic tant à court qu’à long terme.Nous avons montré que la restriction de croissance intra-utérine était associée au pronostic neurologique des grands prématurés en terne de déficience cognitive et difficultés scolaires essentiellement et ce même pour des prématurés modérés et une restriction de croissance peu sévère et que l’effet du retard de croissance était modulé selon l’âge gestationnel de naissance. Concernant la croissance extra-utérine, nous avons montré qu’elle était elle-même associée au pronostic neurologique des prématurés mais que cet effet était variable selon la croissance anténatale.Enfin, nous nous sommes interrogés sur les conséquences à court terme des efforts faits par les néonatologistes afin d’optimiser la croissance post-natale des prématurés par une revue de la littérature et montré qu’ils existaient des anomalies métaboliques engendrées par une nutrition agressive qu’il convenait de surveiller.Our main objectives were to define intrauterine growth restrictions in preterm infants to study its consequences in terms of neonatal morbidity and long-term prognosis and also assessment to study the relationship between intrauterine growth restriction, extra-uterine growth and neurological outcomes.We showed initially that strict threshold definition of a "small for gestational age" preterm could not be limited in the context of prematurity in the 10th percentile, but extend beyond, at least to the 20th percentile. Furthermore, to define growth restriction studying, weight was not enough. A definition by the association between weight and head circumference was relevant in terms of prognosis in both the short and long term.We found that growth restriction in very preterm and neurological outcome were significantly associated. Small for gestational age preterm infants were more likely to have cognitive impairment and school difficulties even for moderate preterm and moderate growth restriction. Gestational age was an important factor that modulates the association between growth restriction and outcome. Concerning extra-uterine growth, we have shown that it was associated with neurological outcome but this effect varied with antenatal growth pattern.Finally, we studied by literature review, the short-term consequences of optimized postnatal growth of premature infants and showed metabolic abnormalities caused by an aggressive nutrition that required necessary monitoring

Le brevet : un instrument d'appropriation des innovations technologiques

[fre] Le brevet, un instrument d'appropriation . Les entreprises ne peuvent rentabiliser leurs dépenses de recherche que si elles sont en mesure de s'approprier les bénéfices de leurs innovations. D'un point de vue légal, le brevet remplit ce rôle en conférant à son détenteur le monopole d'exploitation de son invention. . La théorie économique s'interroge sur les conséquences de ces monopoles - concurrence induite par la course aux brevets entre les entreprises, non-optimalité de l'effort de recherche - et sur les moyens d'y remédier. . des innovations technologiques . Dans les faits, le brevet ne garantit pas toujours l'appropriation technologique à leurs inventeurs : certaines innovations ne sont pas entièrement brevetables, les brevets sont souvent contoumables et les contrefaçons possibles. Mais les limites du brevet pourraient n'avoir qu'une influence modérée sur les incitations à innover ; l'imitation, longue et coûteuse, ne réduit que partiellement les bénéfices de la recherche pour les innovateurs. [eng] The Patent, a Means of Owning Technological Innovations . Companies can only make their research expenditure pay if they are able to reap the profits of their innovations. The patent fulfils this role from a legal point of view by giving its holder a monopoly over the use of his invention. . Economic theory is probing the consequences of these monopolies - such as the competition generated by firms joining the race to patent and also research not being developed to the utmost - and is examining ways of remedying the situation. . A patent does not always guarantee its inventors technological ownership in practice: some innovations are not entirely patentable and patents can often be circumvented and infringed. Yet the patent's limits should only really have a moderate influence on incentives to innovate; time-consuming and expensive imitations only partially reduce the profits from the research for the innovators. [spa] La patente, una herramienta de apropiaciôn de las innovaciones tecnolôgicas . Las empresas solo pueden rentabilizar sus gastos de investigation si son capaces de apropiarse los beneficios de sus innovaciones. Desde el punto de vista legal, la patente desempena este papel al otorgarle a quien la posée el monopolio de explotaciôn de la propia invention. . La teoria econômica considéra las consecuencias de dichos monopolios - competencia inducida por la rivalidad por las patentes entre empresas, no optimalidad del esfuerzo de investigation - y sus remedios. . En la realidad, la patente no siempre les garantiza la apropiaciôn tecnôlogica a sus inventores : ciertas innovaciones no son del todo patentables, las patentes a menudo se pueden evitar, y son posibles las falsificaciones. Con todo, los limites de la patente parecen tener solo una influencia reducida sobre las incitaciones a innovar ; la imitation, larga y costosa, apenas reduce de manera muy limitada los beneficios de la investigation para los innovadores.

Devenir neurologique et scolaire à 5 et 8 ans des nouveau-nés prématurés " petit pour l'âge gestationnel" (à partir de la cohorte épipage)

Etudier les liens chez des enfants prématurés entre le poids pour l âge gestationnel (AG) et la mortalité néonatale et le devenir neurologique et scolaire à 5 et 8 ans. 2846 prématurés nés en 1997 entre 24 et 32 semaines d aménorrhée (SA) ont été inclus (étude EPIPAGE). A 5 ans, 1812 examens neurologiques, 1535 évaluations cognitives par le K-ABC et 1680 évaluations comportementales par le Strenght and Difficulties Questionnaire et à 8 ans, 1444 questionnaires parentaux sur la scolarisation ont été recueillis. Le poids pour l AG à été défini sur la cohorte: très petit poids pour l AG (TPP-AG) = 20ème percentile. Les relations entre le poids pour l AG et le devenir ont été analysées puis quantifiées après ajustement sur des facteurs de confusion potentiels. Dans le groupe des 24-28 SA, la mortalité était significativement (p < 0,01) augmentée chez les enfants TPP-AG (62%) et PP-AG (42%) par rapport aux PA-AG (30%). Dans le groupe des 29-32 SA, comparé aux PA-AG, le TPP-AG était associé à une augmentation significative de la mortalité OR = 2,79 [IC 95% 1,50-5,20], des déficiences cognitives OR = 1,73 [IC 95% 1,12-2,69] et des troubles d inattention-hyperactivité (OR = 1,78 [1,10-2,89]). Le PP-AG était associé à une augmentation des troubles cognitifs (OR = 1,87 [IC 95% 1,24-2,82]) et des troubles du comportement global (OR =1,66 [IC 95% 1,04-2,62]). Parmi les enfants nés prématurés, la restriction de croissance même modérée est associée à la mortalité, au devenir cognitif et comportemental ainsi qu aux difficultés scolaires.PARIS-JUSSIEU-Bib.électronique (751059901) / SudocSudocFranceF

Evaluation in vivo et in vitro d'un biomarqueur urinaire de la fonction du transporteur MRP2

PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Niveau de preuve du suivi thérapeutique pharmacologique du méthotrexate au décours de son administration à haute-dose

Le suivi thérapeutique pharmacologique du méthotrexate est assez unanimement proposé lorsque ce médicament est administré à haute dose (> 1 g/m2) dans divers protocoles de chimiothérapie. Cette pratique, qui fait effectivement l’objet de recommandations figurant dans le résumé des caractéristiques du produit des spécialités correspondantes, repose sur un faisceau d’arguments cliniques montrant un lien entre des concentrations élevées et le risque de toxicité. L’analyse de la littérature confirme qu’il existe des valeurs seuil à divers temps de prélèvements, au-delà desquelles le risque de toxicité augmente. Le résultat du dosage est utilisé pour adapter les mesures de sauvetage par administration d’acide folinique et/ou intensification de l’hyperhydratation alcaline. Le bénéfice effectivement apporté par la mise en œuvre de ces mesures n’a pas été démontré par des études comparatives mais la comparaison aux données historiques montre que l’incidence des toxicités sévères a considérablement diminué depuis qu’elles sont systématiquement mises en oeuvre. La réalisation systématique du dosage sanguin du méthotrexate au décours de son administration permet également d’objectiver ou de confirmer une surexposition franche, situation nécessitant une prise en charge particulière immédiate, notamment par l’administration de carboxypeptidase

Molecular model of the ferroportin intracellular gate and implications for the human iron transport cycle and hemochromatosis type 4A

International audienceFerroportin 1 (FPN1) is a major facilitator superfamily transporter that is essential for proper maintenance of human iron homeostasis at the systemic and cellular level. FPN1 dysfunction leads to the progressive accumulation of iron in reticuloendothelial cells, causing hemochromatosis type 4A (or ferroportin disease), an autosomal dominant disorder that displays large phenotypic heterogeneity. Although crystal structures have unveiled the outward- and inward-facing conformations of the bacterial homolog Bdellovibrio bacteriovorus Fpn (or Bd2019) and calcium has recently been identified as an essential cofactor, our molecular understanding of the iron transport mechanism remains incomplete. Here, we used a combination of molecular modeling, molecular dynamics simulations, and Ala site-directed mutagenesis, followed by complementary in vitro functional analyses, to explore the structural architecture of the human FPN1 intracellular gate. We reveal an interdomain network that involves 5 key amino acids and is likely very important for stability of the iron exporter facing the extracellular milieu. We also identify inter- and intradomain interactions that rely on the 2 Asp84 and Asn174 critical residues and do not exist in the bacterial homolog. These interactions are thought to play an important role in the modulation of conformational changes during the transport cycle. We interpret these results in the context of hemochromatosis type 4A, reinforcing the idea that different categories of loss-of-function mutations exist. Our findings provide an unprecedented view of the human FPN1 outward-facing structure and the particular function of the so-called "gating residues" in the mechanism of iron export.-Guellec, J., Elbahnsi, A., Le Tertre, M., Uguen, K., Gourlaouen, I., Férec, C., Ka, C., Callebaut, I., Le Gac, G. Molecular model of the ferroportin intracellular gate and implications for the human iron transport cycle and hemochromatosis type 4A